The human inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC), affect over 1 million Americans. Until recently, therapies for these disorders have non-specifically suppressed the immune response to inhibit intestinal inflammation. Specific understanding of immune pathways has led to the development of TNF blockade as a treatment for CD and possibly UC. However, this biological intervention is only effective in a minority of patients, and is associated with short and long term toxicities. Therefore, significant unmet medical needs exist in these debilitating human diseases. A preponderance of experimental results highlights the importance of the NF-KB family of transcription factors in the initiation and perpetuation of chronic inflammation in IBD. The purpose of this Phase I STTR is to provide preclinical efficacy and mechanistic data to support the development of a novel cell permeable NF-KB inhibitory peptide for the treatment of IBD. Investigators at the applicant organization, TheraLogics, Inc., have been at the forefront of NF-KB research and hold an intellectual property position on the NF-KB inhibitor. This inhibitor to be developed is a short peptide comprised of an 8 lysine protein transduction domain (PTD) with an IKB kinase (IKK) inhibitory sequence, "NF-KB essential modulator" (NEMO) binding domain (NBD) (collectively referred to as PTD-NBD). Compared to other NF-KB inhibitors in development for chronic inflammatory diseases, PTD-NBD has the advantages of: (i) inhibiting activated NF-KB, a hallmark of chronic inflammation, (ii) not inhibiting basal NF-KB activity which may be involved in fundamental cellular processes distinct from inflammation, (iii) having pharmacodynamic effects which outlast its pharmacokinetic properties, and (iv) the potential for systemic and local delivery. The collaboration with the University of Pittsburgh combines investigators with expertise in and intellectual property for the delivery of cell permeable peptides in inflammatory diseases with a leading group in basic and clinical IBD research. Experiments in this proposal will provide the preclinical and pharmacodynamic data to support the development of PTD-NBD in later phase studies as a potential therapy for human IBD. Relevance of this research to public health: The human IBDs, CD and UC, affect over 1 million Americans. There are many pressing, unmet medical needs to develop safer and more effective treatments for these lifelong, debilitating illnesses. In this application, investigators at TheraLogics, Inc., and the University of Pittsburgh propose to test a new treatment in mouse models of IBD that can potentially be administered by mouth and works by turning off a protein, NF-KB, which is a "master switch" that turns on inflammation in the intestine. If these studies are successful, future studies will be designed to assess the safety of this new compound, and rapidly develop this treatment to evaluate in people with IBD. [unreadable] [unreadable] [unreadable] [unreadable]